Healing of rat femoral segmental defect with bone morphogenetic protein-2: a dose response study.

Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
Journal of musculoskeletal & neuronal interactions (Impact Factor: 2.45). 03/2012; 12(1):28-37.
Source: PubMed

ABSTRACT Use of recombinant human bone morphogenetic protein-2 (rhBMP-2) is becoming a common clinical approach to enhance bone repair. There is little or no information in the literature on the dose of rhBMP-2 required for effective healing of critical-sized defects such as those associated with trauma. In this study, we used a segmental defect model to assess the dose response of rhBMP-2 using quantitative and qualitative endpoints.
Femoral defects in rats were replaced with absorbable collagen sponges carrying rhBMP-2 (0, 1, 5, 10 or 20 μg; N=5). At 4-weeks new bone formation was assessed using quantitative (radiography and microcomputed tomography) and qualitative (histology and backscattered-SEM) endpoints statistically compared.
rhBMP-2 showed increased bridging in the gap. Quantitative evaluation presented a bi-phasic dose response curve. Histological assessment revealed that with rhBMP-2 the defect showed the presence of spongy bone with the trabeculae layered with active osteoblasts and osteoclasts. The density and compactness of the bone varied with the dose of rhBMP-2.
Our findings revealed that all doses of rhBMP-2 result in new bone formation. However, there is an optimum dose of 12 μg of rhBMP-2 for bone repair in this model, above which and below which less stimulation of bone occurs.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Porous titanium scaffolds are a promising class of biomaterials for grafting large bone defects, because titanium provides sufficient mechanical support while its porous structure allows bone ingrowth resulting in good osseointegration. To reinforce porous titanium scaffolds with biological cues that enhance and continue bone regeneration, scaffolds can be incorporated with bioactive gels for time and dose controlled delivery of multiple growth factors (GFs). In this study, critical femoral bone defects in rats were grafted with porous titanium scaffolds incorporated with nanostructured colloidal gelatin gels. Gels were loaded with bone morphogenetic protein-2 (BMP-2, 3 µg), fibroblast growth factor-2 (FGF-2, 0.6 µg), BMP-2 and FGF-2 (BMP-2/FGF-2, ratio 5:1) or were left unloaded. GF delivery was controlled by fine-tuning the cross-linking density of oppositely charged nanospheres. Grafted femurs were evaluated using in vivo and ex vivo micro-CT, histology, and three-point bending tests. All porous titanium scaffolds containing GF-loaded gels accelerated and enhanced bone regeneration: BMP-2 gels gave an early increase (0-4 weeks), and FGF-2 gels gave a late increase (8-12 weeks). Interestingly, stimulatory effects of 0.6 µg FGF-2 were similar to a five-fold higher dose of BMP-2 (3 µg). BMP-2/FGF-2 gels gave more bone outside the porous titanium scaffolds than gels with only BMP-2 or FGF-2, resulted in bridging of most defects and showed superior bone-implant integrity in three-point bending tests. In conclusion, incorporation of nanostructured colloidal gelatin gels capable of time and dose controlled delivery of BMP-2 and FGF-2 in porous titanium scaffolds is a promising strategy to enhance and continue bone regeneration of large bone defects.
    Tissue Engineering Part A 07/2013; · 4.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone regeneration is one of the focus points in the field of regenerative medicine. A well-known stimulus of bone formation is bone morphogenetic protein-2 (BMP-2), which has already been extensively used in clinical applications. However due to a short half-life, supraphysiological doses are applied resulting in severe side effects such as ectopic bone formation or even loss of bone. We compared the effectivity of transient BMP-2 gene delivery with BMP-2 protein at clinical (high) and physiological (low) doses by subcutaneous implantation of alginate-based constructs in mice. After 6 weeks of implantation, both the protein-laden constructs and BMP-2 plasmid DNA-based constructs showed similar early bone onset and elevated bone formation compared to controls without any BMP-2 added. We found no differences in efficiency by using BMP-2 plasmid DNA or any of the BMP-2 protein dosages. Therefore we conclude that BMP-2 plasmid DNA based gene therapy in alginate is a promising new strategy for BMP-2 administration for bone (re)generation.
    Tissue Engineering Part A 07/2013; · 4.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously showed that transplantation of adipose-derived stem cells (ASCs) engineered with hybrid baculovirus persistently expressing BMP2/VEGF into segmental defects in New Zealand White (NZW) rabbits led to successful defect reunion. By using micro-computed tomography (μCT) and histology, here we further demonstrated that transplanting the hybrid baculovirus-engineered ASCs into the massive defects (10 mm in length) at the femoral diaphysis of NZW rabbits resulted in trabecular bone formation in the interior via endochondral ossification and bone remodeling at 3 months post-transplantation. The progression of bone remodeling gave rise to the resorption of trabecular bone, conspicuous reconstruction of medullary cavity and cortical bone with lamellar structure at 8 months post-transplantation, hence conferring mechanical properties that were comparable to those of non-operated femora. Importantly, X-ray, positron emission tomography/computed tomography (PET/CT) scans and histopathology revealed no signs of heterotopic bone formation and tumor formation. These data altogether attested that the genetically engineered ASCs and prolonged BMP2/VEGF expression not only healed and remodeled the stringent segmental defects, but also revitalized the defects into living bone tissues that structurally and biomechanically resembled intact bones without appreciable side effects, making it one step closer to translate this technology to the clinical setting.
    Tissue Engineering Part A 12/2013; · 4.64 Impact Factor

Full-text (2 Sources)

Available from
May 20, 2014